Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response

Menée notamment à partir d'échantillons de cellules mononucléées du sang périphérique provenant de patients atteints d'un mélanome de stade IV, cette étude analyse les mécanismes d'action des inhibiteurs de PD-1 et de CTLA-4

Résumé en anglais

Despite the success of checkpoint-targeting therapies, many melanoma patients do not respond or acquire resistance after initial responsiveness. A better understanding about the mechanism by which these therapies enhance immune-mediated tumor control is key to providing the rationale for better treatment strategies. In this study, we show that PD-1 blockade does not modulate the breadth or the magnitude of the circulating tumor-reactive CD8 T cell response. In contrast and in concordance with our previous study, CTLA-4 blockade leads to a broadening of the circulating melanoma-reactive CD8 T cell response. Together, these findings show differential mechanisms of action of CTLA-4 and PD-1 blockade and support the synergy of the combination treatment seen in the clinic.Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1 blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral blood. If the activation of circulating, tumor-reactive T cells would form an important mechanism of action of PD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 T cell responses toward 71 melanoma-associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the circulating melanoma-reactive CD8 T cell response was unaltered upon PD-1 blockade. In contrast, a broadening of the circulating melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. Based on these results, we conclude that PD-1 and CTLA-4 blockade have distinct mechanisms of action. In addition, the data provide an argument in favor of the hypothesis that anti–PD-1 therapy may primarily act at the tumor site.